Although most HIV-1-infected individuals develop disease within 10 years, others remain symptom-free for prolonged periods. Most long-term healthy survivors of HIV-1 infection still manifest evidence of disease progression in the form of declining CD4+ lymphocyte concentrations. However, some rare individuals are not only long-term healthy survivors but also nonprogressors in that they maintain stable levels of CD4+ T lymphocytes in the normal or near normal range. Although various definitions of nonprogressors have been used, approximately 5% of seropositive men have shown no declines in CD4+ cell numbers or HIV-related disease despite ten or more years of documented HIV-1 infection. There is considerable interest in studying the long-term, nonprogressing survivors of HIV-1 infection in order to better understand the mechanisms by which HIV-1 infection can be controlled. Viral and/or host factors are suspected to be responsible for the lack of progression in at least some individuals. Host factors may include the inherent susceptibility of an individual's cells for supporting HIV-1 replication or an HLA-determined ability to mount an adequate immune response. Since most HIV-1 infections appear to result from only one or a few infectious virus particles, we reasoned that partially defective or attenuated strains of HIV-1 may be all that is transmitted in some cases. We have focused our initial studies on the HIV-1 auxiliary gene called nef. Nef is not required for virus replication in cell culture but in SIV it is required for the development of AIDS in rhesus monkeys.8 The function of nef has not yet been clearly defined. In the results described in this brief report, HIV-1 nef gene sequences were amplified from five individuals who have shown no signs of HIV-1 disease progression or declines in CD4+ T-lymphocyte concentrations over more than ten years of infection. Thirty-four of 34 positive reactions from blood samples obtained in 1983, 1986, 1989 and 1993 from one individual yielded only deleted, defective forms of nef. The clinical and virologic characteristics of the HIV-1 infection in this individual are strikingly similar to the characteristics of rhesus monkey infection with a strain of SIV deleted in nef. Full-size nef genes predominated in the other four subjects. These results indicate that infection with nef-defective, attenuated forms of HIV-1 contributes to the lack of disease progression in some individuals.